The work done in this project has been an integral part of a team effort with NCI and NIAID laboratories to develop new inhibitors of HIV that target the highly conserved nucleocapsid protein (NCp7). The Bioorganic Chemistry Section has the responsibility to design the actual drug candidates and to direct and participate in their synthesis. As reported last year, we began exploring a number of variants of dithiobis(benzamides), a class of compounds previously shown by our group and others to selectively inactivate NCp7 through covalent modification of its zinc finger cysteines. In the course of this work, we synthesized other chemotypes and discovered that certain thioesters showed considerable promise as antiviral agents as tested by in vitro assays for zinc ejection from recombinant NCp7, HIV antiviral potency (XTT test), and cellular toxicity. Some of these compounds, because of their low toxicity, exhibited very good therapeutic indices (low toxicity coupled with good potency). We have synthesized and screened a panel of the thioesters, exploring various aspects of structure in relation to function. In particular, we identified a subclass of thioesters that bear a pyridinium cationic group, the pyridinioalkanoyl thioesters. Their low molecular weight and stability toward glutathione highlight potential advantages over the dithiobis(benzamides) and derivative benzisothiazolones, especially in regard to bioavailability and in vivo efficacy. A worldwide patent (PCT) was filed during the past year covering the 2-mercaptobenzamide thioester chemotype as anti-HIV candidates active in inhibiting the nucleocapsid zinc finger structures. The patent covers other possible applications, including the inactivation of other retroviruses.